This application represents the competitive continuation of the Merit Award R37-AR32081 that is funded until June 20, 2000. During the last 10 years of funding we have completed several relevant studies on pemphigus vulgaris (PV), non-endemic pemphigus foliaceus (PF), endemic PF [also known as Fogo Selvagem (FS)] and Bullous Pemphigoid (BP) that are summarized as follows: a) we have developed animals models of PV , PF, and FS by passive transfer of patients' IgG, b) we have developed affinity-chromatography procedures to purify autoantibodies from PF, PV, and BP sera, c) we have developed a highly sensitive and specific ELISA to detect PF, PV, and BP autoantibodies using recombinant proteins, d) we have characterized a human settlement with a high prevalence of endemic FS (3 percent) in a Brazilian Indian Reservation, e) we have studied in this reservation 5 FS cases in the pre-clinical stage and several normal controls that exhibit moderate titers of anti-dsg1 IgG autoantibodies, predominantly IgG1. These autoantibodies increased several fold when FS was fully established, and the predominant IgG isotype was IgG4, f) we have been able to clone antigen-specific T cells from peripheral blood of FS patients from this Indian reservation. In addition, g) we mapped the hemidesmosome as the target of BP autoantibodies, h) we discovered and characterized the BP180 antigen as a component of hemidesmosomes, i) we developed the first animal model of BP by passive transfer of anti-BP antibodies. In this grant we hypothesize that in FS anti-dsg1 autoantibodies of the IgG1 and IgG4 subclass may differ in their pathogenicity and epitope-specificity. To test this hypothesis we will isolate and study dsg1-specific IgG1 and IgG4 from FS sera, clone and sequence V genes from B cells of these patients by single cell RT-PCR, develop monoclonal anti-idiotypic antibodies, generate recombinant anti-dsg1 Fabs, and carry out dsg1 epitope mapping studies. Similar studies will be performed with anti-dsg3 autoantibodies in PV. These studies may lead to new therapies for these serious cutaneous autoimmune diseases.